Dysregulated circadian rhythms, including the sleep/wake cycle, are increasingly appreciated as a key pathophysiological factor involved in Alzheimer's disease (AD). While growing evidence points to a role of sleep in regulating amyloid accumulation, whether and by what mechanisms the cardinal circadian clock, with the molecular oscillator at its core, contributes to AD pathology and disease progression remains not well understood. Disruption of the circadian clock has been shown to cause dysregulated gene expression and neurodegeneration, and recent studies indicated adverse impact on amyloid dynamics in mice lacking the core clock component BMAL1. These findings, together with our recent pharmacological studies, provide initial proof for a direct regulatory function of the core oscillator in AD. In the current application, we propose to test the central hypothesis that the circadian oscillator is a modifiable factor for AD progression; specifically, enhancing circadian oscillation may serve as an interventional strategy against AD via oscillator-regulated gene expression and protein aggregation. Combining a team of circadian clock and AD experts, we propose three specific aims. In Aim 1, we will address the question whether components of the oscillator, specifically the negative arm of the core loop or the stabilization loop, modulate AD progression. We will characterize longitudinal circadian degeneration in both genetic and sporadic AD mouse models. We will generate compound circadian KO/AD mouse lines and determine whether disruption of oscillator components aggravates behavioral and pathological impairments in AD mice. In Aim 2, we will address the hypothesis that activation of the oscillator can be deployed as an interventional strategy against AD progression. We will use both pharmacological (a clock-enhancing small molecule) and genetic (mice with rhythmic overexpression of PER2) enhancement of circadian amplitude to determine beneficial effects of circadian activation on AD progression. We will further delineate the molecular mechanism of circadian expression of genes required for Abeta dynamics. In Aim 3, we will investigate whether the circadian oscillator regulates amyloid and tau protein aggregation via mitochondria/ROS control. We will use both in vivo and in vitro model systems to determine whether an oscillator-enhancing pharmacological agent or oscillator components regulate the formation of Abeta and tau protein aggregates. Effects on ROS control and mitochondrial respiration will be investigated in mechanistic studies. We will employ mass-spec approaches for quantification of different Abeta and tau species and identification of proteomic changes. The innovations of this project include a novel conceptual framework of the circadian oscillator as a modifiable causal factor against AD, the interventional strategy of activating the oscillator to delay AD progression, and the elucidation of new molecular and cellular mechanisms linking the oscillator and AD/protein aggregation. The studies will have both basic and translational impact, and may ultimately lead to a new paradigm of targeting circadian machinery to improve neuropathological and behavioral deficits in AD and fundamentally retard disease progression.